Critical Role of TLR9 in Acute Graft-versus-Host Disease

Abstract

Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9 ؊/؊ ) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4 ؊/؊ ) mice. The reduced mortality and morbidity in TLR9 ؊/؊ mice related with reduced stimulatory activity of TLR9 ؊/؊ spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9 ؉/؉ into TLR9 ؊/؊ and TLR9 ؊/؊ into TLR9؉/؉ chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9 ؉/؉ cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.

Toll-like receptor 9, NOD2 and IL23R gene polymorphisms influenced outcome in AML patients transplanted from HLA-identical sibling donors

“…Therefore, TLR9 is often involved in a variety of immune responses arising at multiple occasions throughout the whole post transplant period, comparable with its involvement in the progression of autoimmune disease such as systemic lupus erythematosus, which can be regarded as a different kind of overwhelming immune response. 14,[24][25][26][27][28][29] Some reports suggest that CpG-rich ODNs as TLR9 ligands are able to induce overwhelming immune responses such as sepsis or systemic inflammatory response syndrome, thus endangering patients after transplant. 25 Studies using C57BL/6 knockout mice showed that TLR9 À/À recipients of grafts had an improved survival and less GVHD after transplant compared with TLR9 þ / þ mice.…”

Novel Small Molecule Inhibitors of TLR7 and TLR9: Mechanism of Action and Efficacy In Vivo

“…This cycle of innate immune recognition, generation of selfreactive antibodies, and enhanced immune complex formation is believed to contribute to the pathogenesis of SLE and possibly Sjogren's syndrome (Marshak-Rothstein, 2006), a finding confirmed in animal models treated with TLR7 and TLR9-competitive antagonist oligonucleotides (Christensen et al, 2005;Barrat et al, 2007). In addition, TLR-mediated pathologic responses to nucleic acids may contribute to other pathologies, such as damage due to liver injury or lung infection, pancreatitis, and graft-versus-host disease (Calcaterra et al, 2008;Bamboat et al, 2010;Hoque et al, 2011;Itagaki et al, 2011). Recent clinical data show that an injectable, synthetic, competitive oligonucleotide inhibitor of TLR9 has efficacy in psoriasis (Kimball et al, 2013).…”

TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…Bone marrow and splenocyte cell suspensions were prepared as previously described. 25 All mice received an oral suspension of gentamicin (320 mg/l) with their drinking water from 7 days before transplantation until 4 weeks after BMT.…”

“…One retrospective study indicated that TLR4 mutations reduced the risk of acute GVHD in humans, 24 but other studies have noted that there was no significant influence of TLR4 on the incidence of GVHD. 25,26 To elucidate the role of TLR4 in acute GVHD, we used TLR4-knockout mice (TLR4 2/2 ) in myeloablative bone marrow and splenocyte cell donor or recipient models and observed the morphology and GVHD extent of the recipient mice after HSCT. We further analyzed the CD80, CD86, CD40 and MHC-II expression levels of (TLR4 ) DC and allogeneic T-cell mixed lymphocyte reaction (MLR).…”